Does the Mutation Type Affect the Response to Cranial Vault Expansion in Children With Apert Syndrome?

Most cases of Apert syndrome are caused by mutations in the FGFR2 gene, either Ser252Trp or Pro253Arg. In these patients, over the last decades, spring-assisted posterior vault expansion (SA-PVE) has been the technique of choice for cranial vault expansion in the Craniofacial Unit of Great Ormond Street Hospital for Children (GOSH), London. The aim of this study was to investigate if there is a difference in preoperative intracranial volume (ICV) in patients with Apert syndrome with Ser252Trp or Pro253Arg mutation and whether these mutations affect the change in ICV achieved by SA-PVE. The GOSH craniofacial SA-PVE database was used to select patients with complete genetic testing and preoperative and postoperative computed tomography scans. ICV was calculated using FSL (FMRIB Analysis Group, Oxford) and adjusted based on Apert-specific growth curves. Sixteen patients were included with 8 having Ser252Trp mutation and 8 having Pro253Arg mutation. The mean preoperative adjusted computed tomography volume for patients in the Ser252Trp group was 1137.7 cm3 and in the Pro253Arg group was 1115.8 cm3 (P=1.00). There was a significant increase in ICV following SA-PVE in all patients (P<0.001) with no difference in mean change in ICV between the groups (P=0.51). Four (50%) patients with Ser252Trp mutation and 3 (37.5%) with Pro253Arg mutations required a second operation after primary SA-PVE. The results demonstrate that regardless of the mutation present, SA-PVE was successful in increasing ICV in patients with Apert syndrome and that a repeat volume expanding procedure was required by a similar number of patients in the 2 groups

Evaluation of PRNP Expression Based on Genotypes and Alleles of Two Indel Loci in the Medulla Oblongata of Japanese Black and Japanese Brown Cattle

BACKGROUND: Prion protein (PrP) level plays the central role in bovine spongiform encephalopathy (BSE) susceptibility. Increasing the level of PrP decreases incubation period for this disease. Therefore, studying the expression of the cellular PrP or at least the messenger RNA might be used in selection for preventing the propagation of BSE and other prion diseases. Two insertion/deletion (indel) variations have been tentatively associated with susceptibility/resistance of cattle to classical BSE. METHODOLOGY/PRINCIPAL FINDINGS: We studied the expression of each genotype at the two indel sites in Japanese Black (JB) and Japanese Brown (JBr) cattle breeds by a standard curve method of real-time PCR. Five diplotypes subdivided into two categories were selected from each breed. The two cattle breeds were considered differently. Expression of PRNP was significantly (p<0.0001) greater in the homozygous deletion genotype at the 23-bp locus in JB breed. Compared to the homozygous genotypes, the expression of PRNP was significantly greater in the heterozygous genotype at the 12-bp locus in JB (p<0.0001) and in JBr (p = 0.0394) breeds. In addition, there was a statistical significance in the PRNP levels between the insertion and the deletion alleles of the 23-bp locus in JB (p = 0.0003) as well as in JBr (p = 0.0032). There was no significance in relation to sex, age, geographical location or due to their interactions (p>0.05). CONCLUSION: Our results suggest that the del/del genotype or at least its del allele may modulate the expression of PRNP at the 23-bp locus in the medulla oblongata of these cattle breeds

Lack of association of cranial lacunae with intracranial hypertension in children with Crouzon syndrome and Apert syndrome: a 3D morphometric quantitative analysis

Purpose Cranial lacunae (foci of attenuated calvarial bone) are CT equivalents ofBcopper beating seen on plain skull radio-graphs in children with craniosynostosis. The qualitative presence of copper beating has not been found to be useful for the diagnosis of intracranial hypertension (IH) in these patients. 3D morphometric analysis (3DMA) allows a more systematic and quantitative assessment of calvarial attenuation. We used 3DMA to examine the relationship between cranial lacunae and IH in children with Crouzon and Apert syndromic craniosynostosis

PRNP Haplotype Associated with Classical BSE Incidence in European Holstein Cattle

Background: Classical bovine spongiform encephalopathy (BSE) is an acquired prion disease of cattle. The bovine prion gene (PRNP) contains regions of both high and low linkage disequilibrium (LD) that appear to be conserved across Bos taurus populations. The region of high LD, which spans the promoter and part of intron 2, contains polymorphic loci that have been associated with classical BSE status. However, the complex genetic architecture of PRNP has not been systematically tested for an association with classical BSE. Methodology/Principal Findings: In this study, haplotype tagging single nucleotide polymorphisms (htSNPs) within PRNP were used to test for association between PRNP haplotypes and BSE disease. A combination of Illumina goldengate assay, sequencing and PCR amplification was used to genotype 18 htSNPs and 2 indels in 95 BSE case and 134 control animals. A haplotype within the region of high LD was found to be associated with BSE unaffected animals (p-value = 0.000114). Conclusion/Significance: A PRNP haplotype association with classical BSE incidence has been identified. This result suggests that a genetic determinant in or near PRNP may influence classical BSE incidence in cattle

A population-specific material model for sagittal craniosynostosis to predict surgical shape outcomes

Sagittal craniosynostosis consists of premature fusion (ossification) of the sagittal suture during infancy, resulting in head deformity and brain growth restriction. Spring-assisted cranioplasty (SAC) entails skull incisions to free the fused suture and insertion of two springs (metallic distractors) to promote cranial reshaping. Although safe and effective, SAC outcomes remain uncertain. We aimed hereby to obtain and validate a skull material model for SAC outcome prediction. Computed tomography data relative to 18 patients were processed to simulate surgical cuts and spring location. A rescaling model for age matching was created using retrospective data and validated. Design of experiments was used to assess the effect of different material property parameters on the model output. Subsequent material optimization—using retrospective clinical spring measurements—was performed for nine patients. A population-derived material model was obtained and applied to the whole population. Results showed that bone Young’s modulus and relaxation modulus had the largest effect on the model predictions: the use of the population-derived material model had a negligible effect on improving the prediction of on-table opening while significantly improved the prediction of spring kinematics at follow-up. The model was validated using on-table 3D scans for nine patients: the predicted head shape approximated within 2 mm the 3D scan model in 80% of the surface points, in 8 out of 9 patients. The accuracy and reliability of the developed computational model of SAC were increased using population data: this tool is now ready for prospective clinical application

An overview of animal prion diseases

Prion diseases are transmissible neurodegenerative conditions affecting human and a wide range of animal species. The pathogenesis of prion diseases is associated with the accumulation of aggregates of misfolded conformers of host-encoded cellular prion protein (PrPC). Animal prion diseases include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) or mad cow disease, transmissible mink encephalopathy, feline spongiform encephalopathy, exotic ungulate spongiform encephalopathy, chronic wasting disease of cervids and spongiform encephalopathy of primates. Although some cases of sporadic atypical scrapie and BSE have also been reported, animal prion diseases have basically occurred via the acquisition of infection from contaminated feed or via the exposure to contaminated environment. Scrapie and chronic wasting disease are naturally sustaining epidemics. The transmission of BSE to human has caused more than 200 cases of variant Cruetzfeldt-Jacob disease and has raised serious public health concerns. The present review discusses the epidemiology, clinical neuropathology, transmissibility and genetics of animal prion diseases

Translocation of silver nanoparticles in the ex vivo human placenta perfusion model characterized by single particle ICP-MS

With the extensive use of silver nanoparticles (AgNPs) in various consumer products their potential toxicity is of great concern especially for highly sensitive population groups such as pregnant women and even the developing fetus. To understand if AgNPs are taken up and cross the human placenta, we studied their translocation and accumulation in the human ex vivo placenta perfusion model by single particle ICP-MS (spICP-MS). The impact of different surface modifications on placental transfer was assessed by AgNPs with two different modifications: polyethylene glycol (AgPEG NPs) and sodium carboxylate (AgCOONa NPs). AgNPs and ionic Ag were detected in the fetal circulation in low but not negligible amounts. Slightly higher Ag translocation across the placental barrier for perfusion with AgPEG NPs and higher AgNP accumulation in placental tissue for perfusion with AgCOONa NPs were observed. Since these AgNPs are soluble in water, we tried to distinguish between the translocation of dissolved and particulate Ag. Perfusion with AgNO3 revealed the formation of Ag containing NPs in both circulations over time, of which the amount and their size in the fetal circulation were comparable to those from perfusion experiments with both AgNP types. Although we were not able to clarify whether intact AgNPs and/or Ag precipitates from dissolved Ag cross the placental barrier, our study highlights that uptake of Ag ions and/or dissolution of AgNPs in the tissue followed by re-precipitation in the fetal circulation needs to be considered as an important pathway in studies of AgNP translocation across biological barriers

Translocation of silver nanoparticles in the ex vivo human placenta perfusion model characterized by single particle ICP-MS

With the extensive use of silver nanoparticles (AgNPs) in various consumer products their potential toxicity is of great concern especially for highly sensitive population groups such as pregnant women and even the developing fetus. To understand if AgNPs are taken up and cross the human placenta, we studied their translocation and accumulation in the human ex vivo placenta perfusion model by single particle ICP-MS (spICP-MS). The impact of different surface modifications on placental transfer was assessed by AgNPs with two different modifications: polyethylene glycol (AgPEG NPs) and sodium carboxylate (AgCOONa NPs). AgNPs and ionic Ag were detected in the fetal circulation in low but not negligible amounts. Slightly higher Ag translocation across the placental barrier for perfusion with AgPEG NPs and higher AgNP accumulation in placental tissue for perfusion with AgCOONa NPs were observed. Since these AgNPs are soluble in water, we tried to distinguish between the translocation of dissolved and particulate Ag. Perfusion with AgNO3 revealed the formation of Ag containing NPs in both circulations over time, of which the amount and their size in the fetal circulation were comparable to those from perfusion experiments with both AgNP types. Although we were not able to clarify whether intact AgNPs and/or Ag precipitates from dissolved Ag cross the placental barrier, our study highlights that uptake of Ag ions and/or dissolution of AgNPs in the tissue followed by re-precipitation in the fetal circulation needs to be considered as an important pathway in studies of AgNP translocation across biological barriers